Innovative Tools and Perspectives in Cough Management: Cancer and Cough
Article information
Abstract
Cough is a prevalent symptom in lung cancer that impairs quality of life. Postoperative cough after pulmonary resection (CAP) has an incidence of approximately 21.1%–55.8%. CAP tends to peak around 1-month post-surgery, and often improves by 3 months. Risk factors for persistent CAP include female sex, extensive resection (e.g., lobectomy or lymph node dissection), and postoperative gastroesophageal reflux. Pulmonary rehabilitation programs significantly reduce postoperative cough incidence and improve cough-specific quality of life. In patients with lung cancer, cough occurs in over 50% of cases, regardless of stage or histology. A stepwise management algorithm is recommended: first treat the cancer and any contributing comorbidities, then use simple demulcents to soothe airways. If needed, add centrally acting antitussives such as codeine or dextromethorphan, followed by peripherally acting agents (e.g., levodropropizine, benzonatate, or levocloperastine). In refractory cases, the neurokinin- 1 (NK1) receptor antagonist aprepitant reduced cough frequency in a randomized trial. Substance P, which activates NK1 receptors in vagal sensory pathways, appears to drive cough; aprepitant blocks this activation in preclinical models. Cough is a common and burdensome symptom in lung cancer, whether post-surgical or disease-related. This narrative review outlines a stepwise approach to evaluation and treatment, starting with cancer-directed therapy and supportive care, followed by evidence-backed antitussives. Emerging therapies like NK1 receptor antagonists show promise for refractory cases. High-quality trials are needed to further validate these approaches and integrate them into standard care to improve the quality of life of patients with lung cancer.
Postoperative Cough after Lung Cancer Surgery
Postoperative cough is common following lung cancer surgery with meta-analyses reporting an incidence of 21.1% to 55.8% [1]. Symptoms typically begin within 1–2 weeks, peak around postoperative day 30, and resolve in most patients by 90 days (Figure 1) [2].
Time course, risk factors, and management of postoperative cough after lung resection. (A) Cough typically begins within 1–2 weeks after surgery, peaks at approximately 1 month, and gradually improves, with resolution in most patients by 90 days postoperatively. (B) Key risk factors associated with postoperative cough, including female sex, larger extent of lung resection, longer operative time, and the presence of gastroesophageal reflux disease (GERD)-related symptoms. (C) Management strategies for postoperative cough. In addition to common antitussive medications, adjunctive gastrointestinal (GI) medications, including proton pump inhibitors, and pulmonary rehabilitation may be beneficial in selected patients.
The associated risk factors are highly diverse (female sex, preoperative cough, right lobe operation, lobectomy, lymph node dissection, closure of the bronchial stump with a stapler, postoperative reflux, and prolonged anesthesia). In general, chronic cough is reported more frequently in women than in men, a difference that has been attributed to the influence of the female sex hormone estrogen [3]. Several studies have shown that patients with prominent postoperative cough have increased expression or activity of transient receptor potential (TRP) channels (particularly TRPV1 and TRPA1) [4]. These channels are closely linked to vagal C-fiber activation, the primary afferents of the cough reflex. Estrogen can sensitize TRPV1 and increase C-fiber excitability, which may explain why women experience postoperative cough more frequently than men [5].
The magnitude of postoperative structural alterations within the thoracic cavity has been found to correlate with an increased risk of cough. Right-sided lung resections typically involve greater anatomic disruption than left-sided ones, and lobectomy causes more structural change than sublobar resections (wedge or segmentectomy); both are associated with a higher risk of postoperative cough [6-9]. Surgical lymph node dissection, whether subcarinal, paratracheal, or mediastinal, can damage vagus nerve branches, further increasing the risk [10]. In addition, stapled closure of the bronchial stump may trigger a foreign-body reaction and chronic inflammation, both contributing to postoperative cough.
Among the various risk factors mentioned above, postoperative acid reflux is regarded as the most important [1,2]. In a study of patients with postoperative cough and acid reflux symptoms, a 2-week course of a proton pump inhibitor (PPI) plus mosapride reduced cough severity, with the visual analog scale (VAS) dropping from 6.5 to 2.3 (p<0.001) [11]. Routine prophylactic use of gastrointestinal medications is not recommended for all patients. However, screening for reflux symptoms in those with persistent postoperative cough is advisable, with targeted treatment considered when reflux is suspected.
Recently, the role of pulmonary rehabilitation (PR) in patients with lung cancer, particularly around surgery, has gained recognition. Pre- and postoperative PR helps preserve lung function and reduce complications. Additionally, perioperative PR appears to directly reduce postoperative cough (p=0.022) and improve health-related quality of life across physical, psychological, and social domains, as measured by the Leicester Cough Questionnaire [12].
In practice, inpatient PR typically includes respiratory training (e.g., incentive spirometry or breathing devices), pursed-lip breathing, directed coughing, assisted sputum expectoration, and stretching exercises targeting the upper thoracic and shoulder girdle muscles. After discharge, these are continued and supplemented with aerobic exercise (e.g., walking or light jogging). Taken together, proactive education and systematic implementation of PR before and after surgery are recommended to optimize pulmonary function, reduce complications, and mitigate postoperative cough, while enhancing overall quality of life.
Common Causes of Chronic Cough: Mechanisms, Clinical Patterns, and Management
Chronic cough, conventionally defined as cough lasting more than 8 weeks, is among the most frequent complaints in outpatient respiratory practice. Before attributing persistent cough to lung cancer or its treatment, clinicians must consider and systematically exclude the common non-malignant etiologies that may coexist in or even predominate in patients with lung cancer. The most prevalent causes are chronic obstructive pulmonary disease (COPD), asthma, post-nasal drip (PND), and gastroesophageal reflux disease (GERD). Each has a distinct pathophysiological mechanism, characteristic clinical presentation, and evidence-based treatment approach. Table 1 provides a structured comparison of the primary mechanisms, clinical presentations, and therapeutic approaches of these common chronic cough etiologies alongside lung cancer (Table 1).
Comparison of common chronic cough causes and lung cancer
1. Chronic obstructive pulmonary disease
In COPD, the dominant driver is airway inflammation, predominantly neutrophilic and macrophage-mediated, caused by long-term exposure to noxious particles (most commonly cigarette smoke or particulate matter). This inflammatory milieu leads to mucus hypersecretion, goblet cell hyperplasia, and mucociliary dysfunction [13]. Excess mucus accumulates in the large and small airways, directly stimulating rapidly adapting receptors (RARs) and C-fibers, triggering the cough reflex. Additionally, structural remodeling (peribronchial fibrosis, airway wall thickening, and loss of lung elastic recoil due to emphysema) further impairs mucociliary clearance and sustains cough [14]. Clinically, COPD-associated cough is typically productive, occurring predominantly in the morning as patients clear nocturnal mucus accumulation, and is often accompanied by dyspnea and exercise limitation [15]. Primary therapeutic approach relies on inhaled bronchodilators which reduce dynamic hyperinflation and improve airflow. Smoking cessation remains the single most effective intervention to slow disease progression and reduce cough burden.
2. Post-nasal drip
PND, also known as upper airway cough syndrome, is one of the most common identifiable causes of chronic cough. The pathophysiological basis involves the drainage of mucus secretions from the nasal mucosa and paranasal sinuses into the hypopharynx and larynx, directly stimulating cough receptors located in the larynx and upper trachea [16]. Several upper airway conditions can contribute to this process, including allergic rhinitis, non-allergic (vasomotor) rhinitis, chronic sinusitis, and rhinitis medicamentosa.
Clinically, patients with PND typically report a sensation of secretions dripping into the throat, frequent throat-clearing, and a nasal or PND quality to cough, often worse in the supine position and upon awakening [17]. The cough is generally non-productive or associated with expectoration of mucoid material from the posterior pharynx. Examination may reveal cobblestoning of the posterior oropharyngeal wall, mucus in the posterior pharynx, or signs of rhinitis or sinusitis on nasal endoscopy. Treatment is directed at the underlying upper airway disorder: antihistamines combined with a decongestant have demonstrated efficacy, likely through anticholinergic reduction of nasal secretions in addition to antihistaminergic effects. Intranasal corticosteroids are the first-line therapy for allergic rhinitis and chronic sinusitis, while nasal saline irrigation serves as a useful adjunct.
3. Gastroesophageal reflux disease
GERD is a well-established cause of chronic cough, accounting for up to 20%–40% of cases. Two principal mechanisms have been proposed. The first is the reflux theory, in which gastric acid reaches the larynx and tracheobronchial tree through microaspiration, directly irritating cough receptors in the subglottis, trachea, and proximal bronchi [18]. The second, and arguably more important, mechanism is the reflex theory: esophageal acidification stimulates distal esophageal vagal afferents, which trigger a vago-vagal reflex arc culminating in cough without actual aspiration of gastric contents [19]. This explains why many patients with GERD-induced cough have no heartburn or regurgitation, and why acid suppression alone does not resolve cough in all cases if non-acid reflux or esophageal hypersensitivity persists.
Clinically, GERD-associated cough tends to worsen after meals, in the recumbent position, and with physical maneuvers that increase intra-abdominal pressure. Cough is typically dry or minimally productive, non-seasonal, and not associated with wheezing. Ambulatory 24-hour multichannel intraluminal impedance-pH monitoring is the gold-standard diagnostic test, enabling correlation of both acid and non-acid reflux events with cough episodes. Empiric treatment with a high-dose PPI for 8 to 12 weeks is often used both diagnostically and therapeutically. Lifestyle modifications, including weight reduction, elevation of the head of the bed, avoidance of fatty or acidic foods, and cessation of smoking and alcohol, are integral components of GERD management [20]. When PPI therapy is insufficient, prokinetic agents may improve lower esophageal sphincter tone and gastric emptying.
Cough in Patients with Lung Cancer: Epidemiology, Assessment, and Stepwise Care
Two large epidemiologic surveys in Korean patients with lung cancer examined presenting symptoms, and in both, cough emerged as the most frequently reported complaint, affecting 38.1%–57.2% of patients [21,22]. Dyspnea, pain, and hemoptysis were also common. Notably, although these other symptoms receive vigorous clinical attention and management, cough has historically attracted a comparatively limited clinical focus, research investment, and therapeutic development, despite its predominance and direct impact on the quality of life, including sleep, nutrition, and communication. More recently, concerted global efforts have emerged to establish the validation, standardization, and clinical applicability of cough assessment methodologies [23].
Cough is a protective reflex designed to clear the airways of irritants, secretions, and foreign material (Table 2 and Figure 2) [24]. It is initiated by mechanical or chemical stimulation of sensory receptors located primarily in the larynx and large airways. These afferent signals are transmitted via the vagus nerve to the brainstem cough center, particularly the nucleus tractus solitarius [25]. The brainstem integrates these inputs and activates efferent motor pathways to generate a coordinated cough response. Central and peripheral modulatory pathways can enhance or suppress the cough reflex, allowing voluntary control to some extent. Pathologic cough arises when these pathways become sensitized or dysregulated, leading to excessive or persistent coughing. The mechanisms underlying cough in patients with lung cancer are complex and cannot be adequately explained by a single pathway [26]. Cough may result from direct mechanical irritation of the airways by a tumor mass involving the large airways. In addition, malignant pleural effusion or pleural invasion by the tumor can induce cough through irritation of the pleural surfaces. Anticancer treatments, including radiotherapy, immune checkpoint inhibitors, and targeted therapies, may further contribute by inducing tumor-related inflammation or treatment-associated pneumonitis, leading to activation of peripheral cough receptors [27]. Exacerbation of pre-existing comorbid conditions, such as COPD, asthma, or GERD, may also play a significant role. Accordingly, the evaluation of cough in patients with lung cancer should be based on a comprehensive assessment of the patient’s overall clinical context rather than attribution to a single mechanistic cause.
Pharmacologic options for chronic cough in lung cancer
Comparison of normal cough reflex and mechanisms of cough in lung cancer. In healthy individuals, cough is a protective reflex initiated by sensory receptor activation in the upper and large airways, transmitted via the vagus nerve to the brainstem cough center. In contrast, cough in lung cancer is multifactorial. Direct tumor involvement of the large airways may cause mechanical irritation and obstruction, whereas pleural invasion or malignant pleural effusion can provoke cough through pleural sensory nerve stimulation. Anticancer therapies and exacerbation of pre-existing comorbidities further contribute to cough generation, underscoring the need for individualized mechanistic assessment. RT: radiotherapy; ICI: immune checkpoint inhibitor; COPD: chronic obstructive pulmonary disease; GERD: gastroesophageal reflux disease.
Cough is the most common symptom in patients with lung cancer irrespective of cancer stage, histologic subtype, age, or smoking status [28]. Even in early-stage, peripherally located lung cancer, cough can present with a pneumonia-like pattern. Its prevalence does not differ significantly between centrally located histologies (e.g., squamous cell or small cell carcinoma) and more peripheral types like adenocarcinoma [29]. Among factors influencing symptom burden, ongoing anticancer therapy is consistently associated with improvement, while comorbidities such as asthma, COPD, and GERD are linked to worsening symptoms [30].
Cough management in patients with lung cancer has been guided by clinical expert guidelines and panel reports that adopt a pyramidal framework [31]. It is a stepwise therapeutic approach (Figure 3) [32,33]. Its first and most important aspects are cancer-directed treatment and comorbidities control. Shrinkage of endobronchial or peritumoral disease through systemic therapy (cytotoxic chemotherapy, targeted treatment, and immune checkpoint inhibitors), radiotherapy, critical airway stenting, or surgical palliation can provide rapid symptomatic relief. Clinicians should systematically identify and treat the coexisting conditions that can provoke or sustain coughing, including COPD, GERD, asthma, and respiratory infections.
A stepwise algorithm for the management of cough in patients with lung cancer. COPD: chronic obstructive pulmonary disease; MAOI: monoamine oxidase inhibitor; SSRI: selective serotonin reuptake inhibitor; SNRI: serotonin–norepinephrine reuptake inhibitor; TCA: tricyclic antidepressant; BPH: benign prostatic hyperplasia; PO: per os, orally; CYP3A4: cytochrome P450 3A4.
The second step involves the use of a simple linctus. In practice, this refers to the readily available over-the-counter cough syrups in Korea, such as simple linctus, butamirate linctus, or glycerin-based linctus formulations. The simple linctus is a demulcent preparation that coats the oropharyngeal and upper airway mucosa, thereby reducing sensory irritation and the urge to cough. As an initial symptomatic treatment, it is generally more effective for irritative upper airway cough than for cough related to lower airway inflammatory disease.
If symptoms persist despite simple linctus, the next step is to consider opiate-derivative antitussives such as codeine, cough syrups, and dextromethorphan. These agents act centrally to suppress the cough reflex, mainly via mu-opioid receptors within the medullary cough center. They often provide relatively rapid and reliable relief; however, because their effects are dose dependent, careful monitoring is required for adverse events such as sedation, constipation, and fatigue.
Next, commonly used options include peripherally acting antitussives such as levodropropizine, benzonatate, and levocloperastine. Levodropropizine modulates coughing by inhibiting peripheral C-fiber activity and reducing neuropeptide release. Benzonatate exerts a local anesthetic effect on airway receptors by blocking voltage-gated Na⁺ channels. Levocloperastine suppresses cough primarily through the inhibition of peripheral sensory nerves and the attenuation of allergic stimuli.
A 2-week oral steroid trial is no longer recommended as part of routine care. Corticosteroids are now recommended when cough is due to radiation pneumonitis, immune checkpoint inhibitor related pneumonitis, or exacerbations of COPD or asthma. The use of steroids alone to control cough in the absence of a steroid-responsive inflammatory condition is not recommended.
Refractory Cough in Lung Cancer: Trial-Grounded Options and Emerging Targets
When patients with lung cancer continue to experience chronic cough despite standard antitussives, empiric use of medications with emerging or off-label evidence may be considered. Broadly, three categories exist: antiepileptic drugs, antidepressants (selective serotonin reuptake inhibitors and tricyclic antidepressants, and antiemetics (selective neurokinin-1 [NK1] receptor antagonist) [34].
The rationale for using antiepileptics in refractory chronic cough is that they fundamentally reduce neuronal activity. The representative agents include diazepam, carbamazepine, gabapentin, and pregabalin. Regarding mechanisms relevant to cough, diazepam enhances inhibitory signaling by binding to central gamma-aminobutyric acid (GABA) receptors; carbamazepine blocks neuronal voltage-dependent sodium channels; gabapentin binds the α2δ subunit of voltage-gated calcium channels to reduce neuronal activity [35]; and pregabalin is a newer analog of gabapentin with similar effects. Among these drugs, diazepam and carbamazepine are now used more commonly as antiepileptics than as antitussives, whereas gabapentin and pregabalin are used in the treatment of refractory chronic cough [36]. In particular, the efficacy and safety of gabapentin have been reported in refractory chronic cough patients without lung cancer [37]. However, no randomized controlled trials (RCT) have evaluated gabapentin’s effectiveness for cough control in patients with lung cancer, so its benefit in this population remains unclear.
Pregabalin, like gabapentin, binds to the α2δ subunit of voltage-gated calcium channels and thereby reduces central neuronal excitability (particularly of sensitized vagal C-fibers) attenuating both pain and cough signaling [38]. Owing to its more rapid onset and more predictable pharmacokinetics compared to gabapentin, pregabalin was anticipated to be advantageous for cough control in patients with lung cancer [39]. Pregabalin was also expected to work as a cough medicine because, like dextromethorphan, it was thought to have a mechanism of action similar to that of glutamate receptor antagonists [40]. However, in a recent randomized, double-blind, placebo-controlled study evaluating pregabalin 300 mg administered over 9 weeks (pregabalin [n=83] vs. placebo [n=83]), the primary outcome, improvement in VAS cough scores, did not differ between the groups (p=0.887) [41]. Notably, systemic cancer-directed therapy emerged as a significant factor associated with cough improvement, underscoring that controlling the tumor is essential for managing cough in these patients.
Antidepressant agents, most notably paroxetine (a selective serotonin reuptake inhibitor) and amitriptyline (a tricyclic antidepressant), have historically been explored as antitussives in refractory chronic cough [42,43]. Although no RCTs have assessed these agents specifically in lung cancer, a single-center retrospective series of paroxetine (n=34) was recently reported [44]. This study was limited by a small sample size and the fact that only half the participants had lung cancer. Nevertheless, 24 of the 34 patients (71%) experienced a moderate to major reduction in cough. Notably, patients with dry cough appeared to benefit most from paroxetine. Thus, in patients with lung cancer with troublesome cough, particularly those with depressive symptoms, paroxetine may be a reasonable and selectively reasonable and effective option.
Among therapies for refractory chronic cough in patients with lung cancer, only antiemetic agents (aprepitant) have been supported by two RCTs [45,46]. Aprepitant is a selective NK1 receptor antagonist. Its antitussive effect is based on the emesis pathway: vagal afferents projecting to the medulla release substance P at synapses, activating NK1 receptors to trigger vomiting, a mechanism that closely parallels the key elements of the cough reflex [47].
Preclinical studies used the NK1 antagonist (FK888) in a pig model where substance P levels [48] were raised by phosphoramidon, an inhibitor of the enzyme that normally breaks down substance P. This increase led to more coughing, which FK888 then reduced, supporting an NK1-driven mechanism. Notably, aerosolized substance P does not reliably cause cough or bronchoconstriction in healthy subjects, suggesting that airway or epithelial injury is necessary for substance P-mediated cough [49]. Patients with lung cancer, like those with bronchiectasis or tuberculosis-destroyed lung, often have structural airway and epithelial damage. In these cases, epithelial disruption may amplify the role of the substance P/NK1 pathway, explaining why aprepitant is a mechanistically plausible and clinically effective option for refractory cough.
The first RCT enrolled patients with advanced lung cancer (stage IV, 88%; stage III, 12%) who had persistent cough despite 2 weeks of standard antitussives. They were randomized 1:1 to receive aprepitant (n=64) or control (n=64) [45]. Aprepitant was given as 125 mg on day 1, then 80 mg on days 2–7, followed by discontinuation. The primary endpoints were improvement on the VAS and the Manchester cough in lung cancer scale (MCLCS), and secondary endpoints included health-related quality of life as assessed using the European Organization for Research and Treatment of Cancer (EORTC) instruments and the incidence of adverse events. The trial met both primary endpoints with p<0.001, demonstrating a robust antitussive effect that was evident by day 3 of treatment and persisted after drug discontinuation. Although there was no significant change in overall quality of life, the cough-specific quality of life domain improved (p=0.017). In addition, there was no increase in grade ≥3 adverse events, so no dose reduction or treatment interruption of aprepitant was required.
The second RCT enrolled patients with advanced lung cancer (stage IV, 50%; stage III, 50%) who continued to experience cough despite 4 weeks of standard antitussive therapy (n=19). Aprepitant was administered according to a standard antiemetic regimen of 125 mg on day 1, followed by 80 mg on days 2 and 3. In addition to symptom scoring, the investigators objectively quantified cough using an acoustic monitoring device (VitaloJAK, Vitalograph Ltd., St. Lenexa, KS, USA) to assess awake, sleep, and 24-hour cough frequency. Efficacy was demonstrated by significant reductions in awake cough frequency (p=0.026) and 24-hour cough frequency (p=0.002), with concomitant improvements in the VAS, MCLCS, and EORTC measures. This demonstrated that cough could be controlled with only 3 days of aprepitant rather than seven. The investigation included a mechanistic ex vivo component. Vagal nerve preparations from guinea pigs (n=5) and humans (n=3) were depolarized with substance P, after which aprepitant was applied. The results revealed that aprepitant attenuated substance P-induced depolarization by 78% in the guinea-pig vagus nerve, and by 94% in the human vagus nerve (both p=0.0145); thus, providing direct physiological evidence that NK1 receptor antagonism can suppress cough-related afferent activation.
Conclusion
Postoperative cough after lung resection follows a predictable arc (onset at 1 to 2 weeks, peak near day 30, and improvement by approximately 90 days). Representative risk factors include postoperative reflux (most important), female sex, preoperative cough, right-sided lobectomy, lymph node dissection, and stapled bronchial stump. Screening for reflux symptoms and a PPI treatment can meaningfully reduce symptoms, and PR further lowers cough incidence and improves cough-specific quality of life. The top priorities in managing cough in patients with lung cancer are effective cancer treatment and the optimization of comorbid conditions, followed by a stepwise escalation from demulcents (simple/glycerin-based or butamirate linctus) to centrally acting agents (codeine or dextromethorphan) and peripherally acting agents (levodropropizine, benzonatate, levocloperastine); notably, empiric oral steroids are not recommended without a steroid-responsive indication. For refractory chronic cough, the use of aprepitant (a selective NK1 receptor antagonist) is supported by randomized trial evidence, whereas pregabalin has not shown efficacy. The usefulness of gabapentin has been demonstrated only in refractory chronic cough not caused by cancer. To date, cough has not received as much attention as other cancer symptoms, and more clinical and research efforts should be focused on this debilitating symptom.
Notes
Authors’ Contributions
Conceptualization: all authors. Methodology: all authors. Formal analysis: all authors. Data curation: all authors. Project administration: all authors. Visualization: all authors. Validation: all authors. Writing - original draft preparation: all authors. Writing - review and editing: all authors. Approval of final manuscript: all authors.
Conflicts of Interest
Juwhan Choi is an early career editorial board member and Sung Yong Lee is an associate editor of the journal, but they were not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported.
Funding
No funding to declare.